RCC1

Summary

RCC1 (regulator of chromosome condensation 1, HGNC:1913) is a protein-coding gene on chromosome 1p35.3, encoding Regulator of chromosome condensation (P18754). Guanine-nucleotide releasing factor that promotes the exchange of Ran-bound GDP by GTP, and thereby plays an important role in RAN-mediated functions in nuclear import and mitosis. It is a common-essential gene (DepMap: required in 99.3% of cancer cell lines).

Enables several functions, including guanyl-nucleotide exchange factor activity; nucleosomal DNA binding activity; and protein heterodimerization activity. Involved in G1/S transition of mitotic cell cycle; regulation of mitotic nuclear division; and spindle organization. Located in chromatin; cytoplasm; and nuclear lumen. Part of protein-containing complex.

Source: NCBI Gene 1104 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 64 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.3% of screened cell lines (common-essential)
• MANE Select transcript: NM_001381865

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1913
Approved symbol	RCC1
Name	regulator of chromosome condensation 1
Location	1p35.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000180198
Ensembl biotype	protein_coding
OMIM	179710
Entrez	1104

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 48 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000373831, ENST00000373832, ENST00000373833, ENST00000398958, ENST00000411533, ENST00000419074, ENST00000427469, ENST00000429051, ENST00000430407, ENST00000434290, ENST00000478232, ENST00000486790, ENST00000649185, ENST00000683442, ENST00000901734, ENST00000901735, ENST00000901736, ENST00000901737, ENST00000901738, ENST00000901739, ENST00000901740, ENST00000901741, ENST00000901742, ENST00000929737, ENST00000929738, ENST00000929739, ENST00000929740, ENST00000929741, ENST00000929742, ENST00000929743, ENST00000929744, ENST00000929745, ENST00000929746, ENST00000929747, ENST00000929748, ENST00000929749, ENST00000929750, ENST00000929751, ENST00000929752, ENST00000929753, ENST00000929754, ENST00000929755, ENST00000929756, ENST00000929757, ENST00000929758, ENST00000929759, ENST00000952992, ENST00000952993, ENST00000952994, ENST00000952995

RefSeq mRNA: 6 — MANE Select: NM_001381865 NM_001048194, NM_001048195, NM_001048199, NM_001269, NM_001381865, NM_001381866

CCDS: CCDS41295

Canonical transcript exons

ENST00000683442 — 13 exons

Exon	Start	End
ENSE00001273554	28536262	28536381
ENSE00001273582	28531803	28531990
ENSE00001273585	28516725	28516867
ENSE00001461694	28508830	28508905
ENSE00003467600	28536747	28536899
ENSE00003478538	28508128	28508160
ENSE00003621347	28529858	28529939
ENSE00003695605	28532171	28532350
ENSE00003696436	28535050	28535146
ENSE00003700481	28535258	28535380
ENSE00003789268	28535871	28536026
ENSE00003919148	28537832	28538989
ENSE00003921727	28506043	28506084

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 93.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.0305 / max 76.8872, expressed in 1653 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1801	194.0813	1818
1813	7.9365	1562
1814	3.0633	1074
1810	0.0307	5

Top tissues by expression

278 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	93.44	gold quality
left testis	UBERON:0004533	93.21	gold quality
ventricular zone	UBERON:0003053	93.18	gold quality
sperm	CL:0000019	92.76	gold quality
male germ cell	CL:0000015	92.08	gold quality
testis	UBERON:0000473	91.29	gold quality
lower esophagus mucosa	UBERON:0035834	91.09	gold quality
islet of Langerhans	UBERON:0000006	90.99	gold quality
ganglionic eminence	UBERON:0004023	90.41	gold quality
mucosa of transverse colon	UBERON:0004991	89.99	gold quality
embryo	UBERON:0000922	89.45	gold quality
stromal cell of endometrium	CL:0002255	89.43	gold quality
esophagus mucosa	UBERON:0002469	88.95	gold quality
oocyte	CL:0000023	88.49	gold quality
rectum	UBERON:0001052	88.17	gold quality
olfactory bulb	UBERON:0002264	86.86	silver quality
lymph node	UBERON:0000029	86.64	gold quality
minor salivary gland	UBERON:0001830	85.78	gold quality
cartilage tissue	UBERON:0002418	85.76	gold quality
mouth mucosa	UBERON:0003729	84.59	gold quality
monocyte	CL:0000576	84.48	gold quality
type B pancreatic cell	CL:0000169	84.27	gold quality
leukocyte	CL:0000738	84.05	gold quality
mononuclear cell	CL:0000842	84.04	gold quality
pancreas	UBERON:0001264	83.99	gold quality
secondary oocyte	CL:0000655	83.98	gold quality
transverse colon	UBERON:0001157	83.80	gold quality
vermiform appendix	UBERON:0001154	83.77	gold quality
smooth muscle tissue	UBERON:0001135	83.73	gold quality
esophagus	UBERON:0001043	83.55	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	22.07
E-MTAB-9801	yes	5.81
E-ANND-3	yes	4.82
E-MTAB-6819	no	267.13

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC, MYCN

miRNA regulators (miRDB)

55 targeting RCC1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-6743-5P	99.48	63.60	721
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-3194-3P	98.83	66.22	1167

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 35)

• RanBP3 associates with the Ran-specific guanine nucleotide exchange factor, regulator of chromosome condensation 1 (RCC1). (PMID:11932251)
• These results indicate that the generation of Ran-GTP in the vicinity of chromosomes by RCC1 is important for the fidelity of mitotic spindle assembly in human cells. (PMID:12194828)
• RCC1 release from chromatin in vitro requires a factor(s) distinct from, or in addition to, Ran (PMID:14565978)
• phosphorylation of the NLS of RCC1 is required to prevent the binding of importin alpha and beta to RCC1, thereby allowing RCC1 to couple RanGTP production to chromosome binding (PMID:15014043)
• This 30 kb deletion contains the exons coding for the RCC1-like domain of RPGR. It is the first report of a macrodeletion that spans the entire RCC1-like domain of RPGR in X-linked retinitis pigmentosa patients (PMID:16052169)
• HSV-1 replication is blocked in cell line tsBN2 encoding a temperature sensitive RCC1 protein. (PMID:17251553)
• Propose bimodal attachment mechanism for RCC1 in which the tail promotes stable RCC1 association with chromatin through DNA binding in an alpha-N-methylation-dependent manner. (PMID:17435751)
• These results show that human RCC1 isoforms have distinct chromatin binding properties, different molecular interactions, and are selectively regulated by phosphorylation, as determined by their different NTRs. (PMID:17855385)
• chromosome 1p36 was established to have linkage for adhd. (PMID:18439570)
• A review of the function and structure of RCC1 and RCC1 superfamily genes and proteins. (PMID:18442486)
• RCC1 undergoes post-translational phosphorylation (PMID:18568422)
• reduced binding affinity of RCC1 to the mitotic chromosome, which led to a reduction of RanGTP level. (PMID:18712773)
• The N-terminal tail of RCC1 is essential for association with DNA but inhibits histone binding. (PMID:18762580)
• Therefore, we propose that RCC1 reads the histone code created by caspase-activated Mst1 to initiate apoptosis by reducing the level of RanGTP in the nucleus. (PMID:19060893)
• The authors find that RCC1 uses a conformationally flexible loop region we have termed the switchback loop in addition to its N-terminal tail to bind to the nucleosome. (PMID:20347844)
• discovery of the first alpha-N-methyltransferase, which we named N-terminal RCC1 methyltransferase (NRMT). (PMID:20668449)
• RCC1 can induce bipolar spindle formation. Remarkably, RCC1 beads oscillate within spindles from pole to pole, a behavior that could be converted to a more typical, stable association by the addition of a kinesin together with RCC1. (PMID:22215983)
• RCC1 facilitates a tight binding between the encephalomyocarditis virus leader and cellular Ran GTPase. (PMID:23536659)
• PI3Kbeta regulates the nuclear envelope through upstream regulation of RCC1 and Ran (PMID:25348717)
• stress can disrupt the Ran gradients through RCC1-dependent and RCC1-independent mechanisms (PMID:25452301)
• RCC1 expression is frequently lost in poorly differentiated gastric cell lines and gastric carcinoma tissues. Loss of RCC1 expression is correlated with tumor differentiation and depth of invasion. (PMID:26823742)
• RCC1 expression enables the proliferation of cells that sustain DNA damage. RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage-induced cell senescence. (PMID:26864624)
• this study has demonstrated that EBNA1 and RCC1 closely associate on the chromosomes during metaphase, suggesting an essential role for the interaction during this phase, perhaps in tethering EBNA1 to mitotic chromosomes. (PMID:28284242)
• Importin alpha3 facilitates the nuclear transport of the Ran guanine nucleotide exchange factor RCC1. (PMID:29042532)
• This study provides first evidence for a mutation in RCC1 as a breast cancer susceptibility allele (PMID:29363114)
• RCC1 regulates KT composition at the metaphase-anaphase transition in a Ran-GTP independent fashion through displacement of Shugoshin-1 and chromosomal passenger complex. (PMID:29464982)
• cyclin-dependent kinase 1 (Cdk1), a known target of E2F1, is involved in G1 checkpoint regulation, as Cdk1 knockdown hindered G1/S progression, while Cdk1 overexpression rescued RCC1 knockdown-mediated effect on G1 cell cycle progression. (PMID:29789527)
• RanBP1 controls the Ran pathway in mammalian cells through regulation of mitotic RCC1 dynamics. (PMID:32594833)
• PRMT6 methylation of RCC1 regulates mitosis, tumorigenicity, and radiation response of glioblastoma stem cells. (PMID:33539787)
• Down-regulation of RCC1 sensitizes immunotherapy by up-regulating PD-L1 via p27(kip1) /CDK4 axis in non-small cell lung cancer. (PMID:33630417)
• Phosphorylation of RCC1 on Serine 11 Facilitates G1/S Transition in HPV E7-Expressing Cells. (PMID:34356619)
• RCC1 Expression as a Prognostic Marker in Colorectal Liver Oligometastases. (PMID:34924821)
• RCC1 functions as a tumor facilitator in clear cell renal cell carcinoma by dysregulating cell cycle, apoptosis, and EZH2 stability. (PMID:37747077)
• A novel DNA methylation signature revealed GDF6 and RCC1 as potential prognostic biomarkers correlated with cell proliferation in clear cell renal cell carcinoma. (PMID:38087057)
• Targeting RCC1 to block the human soft-tissue sarcoma by disrupting nucleo-cytoplasmic trafficking of Skp2. (PMID:38561375)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rcc1	ENSDARG00000037158
mus_musculus	Rcc1	ENSMUSG00000028896
rattus_norvegicus	Rcc1	ENSRNOG00000050106
drosophila_melanogaster	Rcc1	FBGN0002638
drosophila_melanogaster	CG7420	FBGN0031344
caenorhabditis_elegans		WBGENE00004304

Paralogs (9): ALS2 (ENSG00000003393), HERC1 (ENSG00000103657), SERGEF (ENSG00000129158), RCBTB1 (ENSG00000136144), RCBTB2 (ENSG00000136161), RPGR (ENSG00000156313), RCCD1 (ENSG00000166965), RCC2 (ENSG00000179051), RCC1L (ENSG00000274523)

Protein

Protein identifiers

Regulator of chromosome condensation — P18754 (reviewed: P18754)

Alternative names: Cell cycle regulatory protein, Chromosome condensation protein 1

All UniProt accessions (10): P18754, A0A0S2Z3I4, A0A0S2Z404, C9J3R0, C9JMJ4, C9JQZ4, C9JRH2, C9JW69, M0R1Q8, Q5T081

UniProt curated annotations — full annotation on UniProt →

Function. Guanine-nucleotide releasing factor that promotes the exchange of Ran-bound GDP by GTP, and thereby plays an important role in RAN-mediated functions in nuclear import and mitosis. Contributes to the generation of high levels of chromosome-associated, GTP-bound RAN, which is important for mitotic spindle assembly and normal progress through mitosis. Via its role in maintaining high levels of GTP-bound RAN in the nucleus, contributes to the release of cargo proteins from importins after nuclear import. Involved in the regulation of onset of chromosome condensation in the S phase. Binds both to the nucleosomes and double-stranded DNA.

Subunit / interactions. Interacts with RAN. Interacts with KPNA3. Interacts (via N-terminus and RCC1 repeats) with KPNA4. Interacts with ARRB2; the interaction is detected in the nucleus upon OR1D2 stimulation.

Subcellular location. Nucleus. Chromosome. Cytoplasm.

Post-translational modifications. N-terminal methylation by METTL11A/NTM1 is required for binding double-stranded DNA and stable chromatin association. Di- and trimethylation produce a permanent positive charge on the amino group, which facilitates electrostatic binding to the phosphate groups on DNA, while inhibiting histone-binding. Methylated tail helps retain RCC1 on chromosomes during nucleotide exchange on Ran.

Disease relevance. Infection-induced acute-onset axonal neuropathy (IIAAN) [MIM:621333] An autosomal recessive disease characterized by the acute onset of axonal neuropathy following infection or febrile illness in infancy or early childhood. Affected individuals present with muscle weakness and reduced reflexes primarily in the lower limbs, although weakness can become more widespread and affect respiratory muscles causing respiratory insufficiency. Progressive cerebral and cerebellar atrophy is seen on brain imaging. The disorder often follows a progressive course, leading to loss of ambulation and the need for long-term ventilatory support. Early death may occur. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Patients with Raynaud disease produce antibodies that bind to RCC1.

Isoforms (2)

UniProt ID	Names	Canonical?
P18754-1	1	yes
P18754-2	2, RCC1-I

RefSeq proteins (6): NP_001041659, NP_001041660, NP_001041664, NP_001260, NP_001368794, NP_001368795 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000408	Reg_chr_condens	Repeat
IPR009091	RCC1/BLIP-II	Homologous_superfamily
IPR051553	Ran_GTPase-activating	Family
IPR058923	RCC1-like_dom	Domain

Pfam: PF25390

UniProt features (79 total): strand 35, mutagenesis site 9, sequence variant 8, repeat 7, helix 6, modified residue 5, compositionally biased region 2, turn 2, initiator methionine 1, chain 1, short sequence motif 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
6DUB	X-RAY DIFFRACTION	1.2
5E1D	X-RAY DIFFRACTION	1.45
5E1B	X-RAY DIFFRACTION	1.65
1A12	X-RAY DIFFRACTION	1.7
5E1M	X-RAY DIFFRACTION	1.75
5E2A	X-RAY DIFFRACTION	1.75
1I2M	X-RAY DIFFRACTION	1.76
5E2B	X-RAY DIFFRACTION	1.95
5E1O	X-RAY DIFFRACTION	2
8UX1	ELECTRON MICROSCOPY	2.5
5TBK	X-RAY DIFFRACTION	3.45

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P18754-F1	93.75	0.91

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5): 2, 2, 2, 2, 11

Mutagenesis-validated functional residues (9):

Position	Phenotype
2	does not abolish n-terminal methylation.
3	abolishes n-terminal methylation.
4	abolishes n-terminal methylation.
4	strongly impairs n-terminal methylation and subcellular localization.
9	decreases kpna4 binding. strongly decreases kpna4 binding; when associated with a-21.
11	phosphomimetic mutant. decreases kpna4 binding by about 10%.
21	decreases kpna4 binding. strongly decreases kpna4 binding; when associated with a-9.
182	abolishes interaction with ran and impairs chromosome localization.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-165054	Rev-mediated nuclear export of HIV RNA
R-HSA-180746	Nuclear import of Rev protein
R-HSA-9615933	Postmitotic nuclear pore complex (NPC) reformation

MSigDB gene sets: 291 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_CHROMOSOME_ORGANIZATION, MODULE_52, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_NUCLEAR_MEMBRANE_REASSEMBLY, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_REGULATION_OF_NUCLEAR_DIVISION, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_MEMBRANE_BIOGENESIS, BROWNE_HCMV_INFECTION_8HR_UP, GOBP_CELL_CYCLE_PHASE_TRANSITION, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, MODULE_16, GOMF_GTPASE_BINDING

GO Biological Process (11): G1/S transition of mitotic cell cycle (GO:0000082), mitotic spindle organization (GO:0007052), chromosome segregation (GO:0007059), mitotic nuclear membrane reassembly (GO:0007084), regulation of mitotic nuclear division (GO:0007088), regulation of mitotic cell cycle (GO:0007346), viral process (GO:0016032), spindle assembly (GO:0051225), cell division (GO:0051301), positive regulation of cell cycle process (GO:0090068), regulation of mitotic spindle assembly (GO:1901673)

GO Molecular Function (10): chromatin binding (GO:0003682), guanyl-nucleotide exchange factor activity (GO:0005085), small GTPase binding (GO:0031267), nucleosome binding (GO:0031491), nucleosomal DNA binding (GO:0031492), histone binding (GO:0042393), sulfate binding (GO:0043199), protein heterodimerization activity (GO:0046982), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (7): chromatin (GO:0000785), condensed nuclear chromosome (GO:0000794), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), cytoplasm (GO:0005737), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Interactions of Rev with host cellular proteins	2
Late Phase of HIV Life Cycle	1
Nuclear Envelope (NE) Reassembly	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitotic cell cycle	4
cellular anatomical structure	3
spindle organization	2
cell cycle process	2
regulation of cell cycle process	2
binding	2
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
microtubule cytoskeleton organization involved in mitosis	1
nuclear membrane reassembly	1
mitotic nuclear membrane organization	1
regulation of mitotic cell cycle	1
regulation of nuclear division	1
mitotic nuclear division	1
regulation of cell cycle	1
biological_process	1
chromosome segregation	1
membraneless organelle assembly	1
cellular process	1
positive regulation of cell cycle	1
regulation of mitotic spindle organization	1
regulation of spindle assembly	1
mitotic spindle assembly	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
GTPase binding	1
chromatin binding	1
protein-containing complex binding	1
chromatin DNA binding	1
nucleosome binding	1
protein binding	1
anion binding	1
sulfur compound binding	1
protein dimerization activity	1
nucleic acid binding	1
chromosome	1
nuclear chromosome	1
condensed chromosome	1
nucleus	1

Protein interactions and networks

STRING

2966 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RCC1	H2AC19	P20670	972
RCC1	H2AC20	Q16777	968
RCC1	H2BC21	Q16778	963
RCC1	RAN	P17080	961
RCC1	RANGAP1	P46060	956
RCC1	KPNA4	O00629	939
RCC1	RABIF	P47224	927
RCC1	RANBP1	P43487	912
RCC1	RANBP3	Q9H6Z4	887
RCC1	KPNA3	O00505	884
RCC1	NTMT1	Q9BV86	878
RCC1	KPNA1	P52294	803
RCC1	XPO1	O14980	789
RCC1	NUTF2	P13662	778
RCC1	RANBP2	P49792	771

IntAct

155 interactions, top by confidence:

A	B	Type	Score
RCC1	RAN	psi-mi:“MI:0407”(direct interaction)	0.950
RAN	RCC1	psi-mi:“MI:0407”(direct interaction)	0.950
RAN	RCC1	psi-mi:“MI:0915”(physical association)	0.950
RAN	RCC1	psi-mi:“MI:0914”(association)	0.950
RCC1	RAN	psi-mi:“MI:0915”(physical association)	0.950
FOXP1	FOXP2	psi-mi:“MI:0914”(association)	0.910
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CCDC93	VPS26C	psi-mi:“MI:0914”(association)	0.640
NEMP1	RGPD8	psi-mi:“MI:0914”(association)	0.640
B2M	NEMP1	psi-mi:“MI:0914”(association)	0.640
RAN	RGPD8	psi-mi:“MI:0914”(association)	0.640
	RCC1	psi-mi:“MI:0407”(direct interaction)	0.620
NTMT1	RCC1	psi-mi:“MI:0213”(methylation reaction)	0.560
NTMT1	RCC1	psi-mi:“MI:0407”(direct interaction)	0.560

BioGRID (311): RCC1 (Affinity Capture-RNA), RCC1 (Affinity Capture-RNA), RCC1 (Affinity Capture-RNA), RCC1 (Affinity Capture-RNA), RCC1 (Affinity Capture-MS), RCC1 (Affinity Capture-MS), RCC1 (Affinity Capture-MS), RCC1 (Affinity Capture-MS), NUSAP1 (Affinity Capture-MS), RGPD3 (Affinity Capture-MS), RGPD8 (Affinity Capture-MS), RANBP2 (Affinity Capture-MS), RGPD5 (Affinity Capture-MS), RANGAP1 (Affinity Capture-MS), RAN (Affinity Capture-MS)

ESM2 similar proteins: B5DG67, B6K1G6, D3ZGQ5, E1BKF9, F1SS88, F4I1S7, O42645, O49326, O93277, P18754, P21827, P23800, P25171, P25183, P28745, P31386, P52499, Q04199, Q18211, Q26613, Q2KIY3, Q5BJ90, Q5F201, Q5PQN1, Q68FJ6, Q6NX08, Q6PAV2, Q6TNS2, Q6ZPR6, Q7ZZC8, Q80YD6, Q86SG6, Q8BHB4, Q8BUB4, Q8H594, Q8N1V2, Q8VE37, Q90XC2, Q91ZR4, Q93XW5

Diamond homologs: A6NED2, F1RD40, F2Z461, O74881, O75592, O95714, P18754, P23800, Q15034, Q4R828, Q4U2R1, Q52KW8, Q5GLZ8, Q5PQN1, Q6NRS1, Q6PAV2, Q7TPH6, Q80YD6, Q8BTU7, Q8IVU3, Q8VE37, Q9FN03, Q9NB71, Q9P2D0, Q9UII4, D3ZGQ5, O95199, P0C5Y8, P25171, P25183, P58544, Q15751, Q5BIW4, Q5DX34, Q5RCZ7, Q6NXM2, Q6NYE2, Q6ZPR6, Q7ZZC8, Q86SG6

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
STK3	up-regulates	RCC1	phosphorylation
CDK1	“up-regulates activity”	RCC1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 141 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Rev-mediated nuclear export of HIV RNA	8	29.2×	2e-07
NEP/NS2 Interacts with the Cellular Export Machinery	7	27.8×	1e-06
Nuclear import of Rev protein	7	27.0×	1e-06
NS1 Mediated Effects on Host Pathways	8	26.2×	2e-07
Transport of Ribonucleoproteins into the Host Nucleus	6	24.6×	1e-05
Postmitotic nuclear pore complex (NPC) reformation	5	23.4×	1e-04
Vpr-mediated nuclear import of PICs	6	23.2×	1e-05
SUMOylation of SUMOylation proteins	6	22.5×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
RNA export from nucleus	5	37.5×	9e-05
NLS-bearing protein import into nucleus	5	32.1×	1e-04
nucleocytoplasmic transport	6	18.8×	2e-04
mRNA export from nucleus	5	11.8×	9e-03
positive regulation of miRNA transcription	5	11.6×	9e-03
protein import into nucleus	10	11.5×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

64 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	45
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2687490	NM_001381865.2(RCC1):c.127G>A (p.Gly43Ser)	Pathogenic
4082220	G43S	Pathogenic
4082224	NM_001381865.2(RCC1):c.781G>A (p.Val261Met)	Pathogenic
2687492	NM_001381865.2(RCC1):c.280A>G (p.Asn94Asp)	Likely pathogenic
2687495	NM_001381865.2(RCC1):c.604G>A (p.Gly202Ser)	Likely pathogenic

SpliceAI

2238 predictions. Top by Δscore:

Variant	Effect	Δscore
1:28508164:AG:A	donor_loss	1.0000
1:28529938:GG:G	donor_gain	1.0000
1:28529939:GG:G	donor_gain	1.0000
1:28535045:TCTAG:T	acceptor_loss	1.0000
1:28535046:CTAG:C	acceptor_loss	1.0000
1:28535047:TAG:T	acceptor_loss	1.0000
1:28535048:A:AG	acceptor_gain	1.0000
1:28535048:AG:A	acceptor_gain	1.0000
1:28535048:AGGAC:A	acceptor_loss	1.0000
1:28535049:G:GG	acceptor_gain	1.0000
1:28535049:GG:G	acceptor_gain	1.0000
1:28535049:GGA:G	acceptor_gain	1.0000
1:28535049:GGAC:G	acceptor_gain	1.0000
1:28535049:GGACA:G	acceptor_gain	1.0000
1:28535250:A:AG	acceptor_gain	1.0000
1:28535251:T:G	acceptor_gain	1.0000
1:28535254:TTAG:T	acceptor_loss	1.0000
1:28535255:TAG:T	acceptor_loss	1.0000
1:28535256:A:AG	acceptor_gain	1.0000
1:28535256:AG:A	acceptor_gain	1.0000
1:28535257:G:GG	acceptor_gain	1.0000
1:28535257:GG:G	acceptor_gain	1.0000
1:28535257:GGA:G	acceptor_gain	1.0000
1:28535257:GGAA:G	acceptor_gain	1.0000
1:28535376:CCTCG:C	donor_gain	1.0000
1:28535377:CTCG:C	donor_gain	1.0000
1:28535377:CTCGG:C	donor_loss	1.0000
1:28535378:TCG:T	donor_gain	1.0000
1:28535379:CG:C	donor_gain	1.0000
1:28535380:GG:G	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000045900 (1:28512974 A>C), RS1000175115 (1:28510822 T>C,G), RS1000178726 (1:28518270 G>C,T), RS1000227428 (1:28510489 T>C), RS1000336370 (1:28517147 T>C), RS1000352153 (1:28530875 T>C), RS1000455780 (1:28524674 A>G,T), RS1000542908 (1:28530217 G>A,T), RS1000576421 (1:28535234 C>T), RS1000578735 (1:28524932 A>G), RS1000628919 (1:28534926 A>G), RS1000635354 (1:28530720 G>A,T), RS1000718042 (1:28505896 G>A,T), RS1000792239 (1:28516870 A>G), RS1000887445 (1:28509812 G>A,T)

Disease associations

OMIM: gene MIM:179710 | disease phenotypes: MIM:621333

GenCC curated gene-disease

Mondo (1): infection-induced acute-onset axonal neuropathy (MONDO:0979881)

Orphanet (0):

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000122	Unilateral renal agenesis
HP:0000218	High palate
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001324	Muscle weakness
HP:0001562	Oligohydramnios
HP:0002059	Cerebral atrophy
HP:0002280	Enlarged cisterna magna
HP:0002283	Global brain atrophy
HP:0002353	EEG abnormality
HP:0002643	Neonatal respiratory distress
HP:0002922	Increased CSF protein concentration
HP:0003584	Late onset
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0006579	Prolonged neonatal jaundice
HP:0006892	Frontotemporal cerebral atrophy
HP:0007002	Motor axonal neuropathy
HP:0007141	Sensorimotor neuropathy
HP:0011342	Mild global developmental delay
HP:0011463	Childhood onset
HP:0011923	Decreased activity of mitochondrial complex I
HP:0100295	Muscle fiber atrophy

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003542_71	Night sleep phenotypes	2.000000e-06
GCST007267_77	Systolic blood pressure	3.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007827	nighttime rest measurement
EFO:0006335	systolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067623 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,478 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1738757	REBASTINIB	2	1,478

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.73	EC50	18.7	nM	REBASTINIB

PubChem BioAssay actives

1 with measured affinity, of 1 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[4-[(3-tert-butyl-1-quinolin-6-ylpyrazol-5-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	2067423: Inhibition of RCC1 (unknown origin)	ec50	0.0187	uM

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
sodium arsenite	decreases expression, increases expression	3
bisphenol A	decreases expression, decreases methylation	2
cobaltous chloride	decreases expression	2
Progesterone	decreases expression	2
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
deoxynivalenol	increases expression	1
sodium arsenate	decreases expression	1
trichostatin A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
beta-methylcholine	affects expression	1
tamibarotene	decreases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
CGP 52608	affects binding, increases reaction	1
AM 251	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	decreases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
bromovanin	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol AF	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5506578	Binding	Inhibition of RCC1 (unknown origin)	RIPK1 inhibitors: A key to unlocking the potential of necroptosis in drug development. — Eur J Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.